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CD30的过表达增强了胸腺中的阴性选择,并通过一条对Bcl-2敏感的途径介导程序性细胞死亡。

CD30 overexpression enhances negative selection in the thymus and mediates programmed cell death via a Bcl-2-sensitive pathway.

作者信息

Chiarle R, Podda A, Prolla G, Podack E R, Thorbecke G J, Inghirami G

机构信息

Department of Pathology and Kaplan Comprehensive Cancer Center, New York University Medical Center, New York, NY 10016, USA.

出版信息

J Immunol. 1999 Jul 1;163(1):194-205.

Abstract

The biological function of CD30 in the thymus has been only partially elucidated, although recent data indicate that it may be involved in negative selection. Because CD30 is expressed only by a small subpopulation of medullary thymocytes, we generated transgenic (Tg) mice overexpressing CD30 in T lymphocytes to further address its role in T cell development. CD30 Tg mice have normal thymic size with a normal number and subset distribution of thymocytes. In vitro, in the absence of CD30 ligation, thymocytes of CD30 Tg mice have normal survival and responses to apoptotic stimuli such as radiation, dexamethasone, and Fas. However, in contrast to controls, CD30 Tg thymocytes are induced to undergo programmed cell death (PCD) upon cross-linking of CD30, and the simultaneous engagement of TCR and CD30 results in a synergistic increase in thymic PCD. CD30-mediated PCD requires caspase 1 and caspase 3, is not associated with the activation of NF-kappaB or c-Jun, but is totally prevented by Bcl-2. Furthermore, CD30 overexpression enhances the deletion of CD4+/CD8+ thymocytes induced by staphylococcal enterotoxin B superantigen and specific peptide. These findings suggest that CD30 may act as a costimulatory molecule in thymic negative selection.

摘要

CD30在胸腺中的生物学功能仅得到部分阐明,尽管最近的数据表明它可能参与阴性选择。由于CD30仅在一小部分髓质胸腺细胞中表达,我们构建了在T淋巴细胞中过表达CD30的转基因(Tg)小鼠,以进一步探讨其在T细胞发育中的作用。CD30转基因小鼠的胸腺大小正常,胸腺细胞数量和亚群分布正常。在体外,在没有CD30连接的情况下,CD30转基因小鼠的胸腺细胞具有正常的存活率,并且对诸如辐射、地塞米松和Fas等凋亡刺激有正常反应。然而,与对照组相比,CD30转基因胸腺细胞在CD30交联后被诱导发生程序性细胞死亡(PCD),并且TCR和CD30的同时结合导致胸腺PCD协同增加。CD30介导的PCD需要半胱天冬酶1和半胱天冬酶3,与NF-κB或c-Jun的激活无关,但被Bcl-2完全抑制。此外,CD30过表达增强了由葡萄球菌肠毒素B超抗原和特异性肽诱导的CD4+/CD8+胸腺细胞的缺失。这些发现表明,CD30可能在胸腺阴性选择中作为共刺激分子发挥作用。

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